Variability and evolution of mandible morphology in Homo sapiens and its ancestors: How did modern morphology evolve in the human mandible? The relationship between static adult allometry and mandibular variability in Homo sapiens: The relevance of late MSA mandibles on the emergence of modern morphology in Northern Africa

Mandibles represent a major part of the hominin fossil record and have been found to carry phylogenetic signals. Late Early until Late Pleistocene mandibular remains offer unique insights into early phases of H. sapiens evolution for which Northwestern Africa provides a series of valuable sites. It is home to the earliest currently known member of Homo sapiens (Jebel Irhoud) and several late Middle Stone Age (MSA) fossils, notably Kébibat, Contrebandiers 1, Dar-es-Soltane II H5 and El Harhoura. The latter three are mostly referred to as “Aterian” and analyzed using geometric morphometrics for the first time. They fill a temporal gap within a long-term succession of hominins in Northern Africa of which we study the best-preserved, namely Tighenif and Thomas Quarry in a comparative framework of other Middle Pleistocene hominins, Jebel Irhoud together with more early H. sapiens from Southern Africa and the Levant, two series of Iberomaurusian H. sapiens from Taforalt and Afalou Bou Rhummel together with other Upper/Late Paleolithic specimens as well as Natufians, Holocene humans, and Neanderthals. Despite the ancient age of early H. sapiens spanning a Middle and early Late Pleistocene timeframe, their upper facial shape falls within the recent human range of variation. In contrast, their mandibles display a mosaic morphology and a unique allometric trajectory that explains aspects of their ‘archaic’ appearance. At the same time, early H. sapiens share a suite of diagnostic features with later H. sapiens that are not related to mandibular size, such as an incipient chin and an anteroposteriorly decreasing corpus height. A mosaic morphology, consisting of a mix between archaic and modern features, was also evident in late MSA fossils of the Maghreb substantiating the view that the emergence of diagnostic H. sapiens traits followed an accretional pattern. Such shift in the frequency of modern traits through time accounts for differences between individuals and Middle/ Late Pleistocene diversity. Our data support the notion that human morphology, currently referred to as ‘modern’, is a gracilized version of an archaic non-Neanderthal pattern and emerged in the course of an ongoing masticatory gracilization process. In this context, structural constraints such as bicondylar and bigonial breadth, affect the expression of shape features as a function of allometric scaling. Among North African fossils, we identified notable similarities in mandibular shape and discrete features through time, suggesting a greater time depth for regional continuity than previously assumed. These results allow us to group Aterians within a single evolving lineage with preceding and succeeding populations in the region, emphasizing North Africa’s role as one of the source areas of the first H. sapiens. Its geographic position at the interface of the Mediterranean Basin and the Sahara makes it a hub of human interaction, shedding light on the nature of potential exchanges with adjacent areas.:Danksagung………….…………………………………………………………………I Bibliographische Darstellung………………………………………………………….II Thesen………………………………………………………………………………… 1 Forschungshintergrund………………………………………………………1 Zielsetzung der Doktorarbeit………………………………………………...3 Überblick Kapitel 1…………………………………………………………..4 Überblick Kapitel 2…………………………………………………………..5 Literatur……………………......…………………………………………….6 Theses………………………………………………………………………11 Research Background………………………………………………………11 Aims of the Thesis………………………………………………….……….13 Overview Chapter 1………………………………………………………...14 Overview Chapter 2………………………………………………………...15 Literature……………………………………………………………………16 Kapitel 1 How did modern morphology evolve in the human mandible? The relationship between static adult allometry and mandibular variability in Homo sapiens …………................………………………..21 Kapitel 2 The relevance of late MSA mandibles on the emergence of modern morphology in Northern Africa………………………………42 Conclusion/Schlussfolgerung……………………………………………...………......55 Appendix Kapitel 1..................................................................................................73 Appendix Kapitel 2..................................................................................................95 Wissenschaftlicher Werdegang.............................................................................116 Selbstständigkeitserklärung..................................................................................119 Nachweis über die Anteile der Co-Autoren............................................................12

Opinions and Treatment Decisions for Dental Erosive Wear: A Questionnaire Survey among Icelandic Dentists

Publisher's version (útgefin grein)Dental erosive wear (DEW) is common among children and adolescents, and a survey of Icelandic children showed that 30.7% of 15-year-olds were diagnosed with the condition. Objective. To gain knowledge about dental practitioners’ experiences, opinions, and treatment decisions. Materials and Methods. A precoded questionnaire, previously used among Norwegian dentists, was sent electronically to all dentists in Iceland (n = 341). Results. The response rate was 64.2%, and 58% of dentists were male. More than half of the clinicians (54%) thought that prevalence had increased the last 10–15 years, and 67% reported it to be more common in male. Most (96%) recorded presence of DEW, but only 4% used a detailed scoring system. Lesions were mostly on occlusal surfaces of first mandibular molars (73%), on palatal in upper anterior teeth (61%), and on occlusal of maxillary first molars (36%). Most dentists (74%) reported a probable cause, e.g., high consumption of carbonated beverages (98%), acidic juices (68%), sport drinks (58%), reflux (54%), and eating disorders (20%). Dietary history was often recorded by 38%, and 65% never measured saliva. Most of the dentists (88%) treated patients themselves, and half of them preferred prevention with high fluoride and resin sealants. While some dentists wanted to restore teeth more invasively, most considered to restore with a filling. Conclusion. Icelandic dentists seem to be well educated for diagnosis and treatment of dental erosion, and dentists are aware of a minimally invasive approach. Clinical Significance. It is challenging for dentists to make the best treatment decision for patients with DEW, both in a short perspective and long perspective. At present, little is known about their knowledge and treatment approach, and there is no standard treatment which can be recommended. Therefore, the present study investigated dental practitioners’ treatment decisions, as well as knowledge, experiences, and awareness of DEW.Peer Reviewe

Cross-sectional study of oral health care service, oral health beliefs and oral health care education of caregivers in nursing homes

© 2021 The Authors. Published by Elsevier Inc.Objectives: To assess oral care beliefs and oral hygiene procedures among nursing home personnel to identify strengths and weaknesses in managing oral care. Methods: A cross-sectional study in two nursing homes using an oral health care questionnaire including the Nursing Dental Coping Belief Scale. Results: A total of 109 health personnel participated. Oral care was seldomly achieved twice a day and dental supplies were not guaranteed. Registered nurses found the oral health of residents more acceptable than did allied health personnel with less oral care education, who mostly delivered daily care. Conversely, nursing staff with oral care education had lower dental coping beliefs, suggesting a lack of self-reliance in controlling oral health outcomes. Conclusion: Dental supplies should be part of nursing care equipment. Educational programs could increase positive oral health beliefs and enhance the quality of care in these settings, particularly among those who are accountable for oral care.Peer reviewe

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive VH81X from both pool

OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67)

Background: Early-onset hearing loss is mostly of genetic origin. The complexity of the hearing process is reflected by its extensive genetic heterogeneity, with probably many causative genes remaining to be identified. Here, we aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family. Methods: A panel of 66 known deafness genes was analyzed for mutations by next-generation sequencing (NGS) in the index patient. We then conducted genome-wide linkage analysis, and whole-exome sequencing was carried out with samples of two patients. Expression of Osbpl2 in the mouse cochlea was determined by immunohistochemistry. Because Osbpl2 has been proposed as a target of miR-96, we investigated homozygous Mir96 mutant mice for its upregulation. Results: Onset of hearing loss in the investigated ADNSHL family is in childhood, initially affecting the high frequencies and progressing to profound deafness in adulthood. However, there is considerable intrafamilial variability. We mapped a novel ADNSHL locus, DFNA67, to chromosome 20q13.2-q13.33, and subsequently identified a co-segregating heterozygous frameshift mutation, c.141-142delTG (p.Arg50Alafs∗103), in OSBPL2, encoding a protein known to interact with the DFNA1 protein, DIAPH1. In mice, Osbpl2 was prominently expressed in stereocilia of cochlear outer and inner hair cells. We found no significant Osbpl2 upregulation at the mRNA level in homozygous Mir96 mutant mice. Conclusion: The function of OSBPL2 in the hearing process remains to be determined. Our study and the recent description of another frameshift mutation in a Chinese ADNSHL family identify OSBPL2 as a novel gene for progressive deafness.</p

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas

A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau

Denisovans are members of a hominin group who are currently only known directly from fragmentary fossils, the genomes of which have been studied from a single site, Denisova Cave in Siberia. They are also known indirectly from their genetic legacy through gene flow into several low-altitude East Asian populations and high-altitude modern Tibetans6. The lack of morphologically informative Denisovan fossils hinders our ability to connect geographically and temporally dispersed fossil hominins from Asia and to understand in a coherent manner their relation to recent Asian populations. This includes understanding the genetic adaptation of humans to the high-altitude Tibetan Plateau, which was inherited from the Denisovans. Here we report a Denisovan mandible, identified by ancient protein analysis, found on the Tibetan Plateau in Baishiya Karst Cave, Xiahe, Gansu, China. We determine the mandible to be at least 160 thousand years old through U-series dating of an adhering carbonate matrix. The Xiahe specimen provides direct evidence of the Denisovans outside the Altai Mountains and its analysis unique insights into Denisovan mandibular and dental morphology. Our results indicate that archaic hominins occupied the Tibetan Plateau in the Middle Pleistocene epoch and successfully adapted to high-altitude hypoxic environments long before the regional arrival of modern Homo sapiens

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing